Epitopes: Types, Function, Epitope Spreading

Epitopes, also known as antigenic determinants, are the immunologically active discrete sites on the antigen molecule that physically bind to antibodies, B-cell receptors, or T-cell receptors.

When an antibody binds to an antigen, it isn’t binding to the entire antigen but to a segment of that antigen known as an epitope. The part of an immunoglobulin that binds and fits the epitope is called a paratope​. Paratope is located at the tip of the variable region of an immunoglobulin, in its antigen-binding site. This paratope is only capable of binding with one unique epitope.

B cells can recognize an epitope alone but T cells can recognize an epitope only when it is associated with an MHC molecule on the surface of a self-cell (either an antigen-presenting cell or an altered self-cell).

An antigen can have one or more epitopes. Most antigens have many determinants (i.e., they are multivalent). In general, antibodies bind epitopes that are roughly five amino acids or sugars in size, whereas T-cell receptors bind epitopes between 8 and 17 amino acids in size.

There may be a presence of related antigens across various species. Related antigens have some epitopes in common but some that are different. Related antigens are also referred to as cross-reacting antigens because antibodies targeted to one antigen are able to react with all other antigens carrying the same epitope.

Functions of Epitopes

Epitope recognition by B-cell and T-cell is central to humoral and cell-mediated immune response.

The humoral branch (B cells) recognizes an enormous variety of epitopes (also referred to as B-cell epitopes): those displayed on the exposed regions of bacteria or viral particles, as well as those displayed on soluble proteins, glycoproteins, polysaccharides, or lipopolysaccharides that have been released from invading pathogens.

When B cells are exposed to T-dependent antigens, they get activated and undergo class switching, affinity maturation, and differentiate into plasma cells. Plasma cells produce large amounts of antibody specific for the epitope recognized by their immunoglobulin receptor.

The cell-mediated branch (T cells) recognizes protein epitopes (also referred to as T-cell epitopes) displayed together with MHC molecules on self-cells, including altered self-cells such as virus-infected self-cells and cancerous cells. As T cells recognize only the processed peptides, those epitopes may be located on those regions (e.g., internal proteins) which are inaccessible to B-cells. Thus, each branch of the immune system uniquely suited to recognize antigen in a different environment.

T-cell epitopes are presented by class I (MHC I) and II (MHC II) MHC molecules that are recognized by two distinct subsets of T-cells, CD8, and CD4 T-cells, respectively. Subsequently, there are CD8 and CD4 T-cell epitopes. T-cells become cytotoxic T lymphocytes (CTL) following T CD8 epitope recognition. Meanwhile, primed CD4 T-cells become helper (Th) or regulatory (Treg) T-cells.

B-cell (left) and T-cell (right) epitope recognition (Image source-Ref-1)
PropertiesRecognized by B cells and AntibodiesRecognized by T cells
CompositionProteins, glycoproteins, polysaccharides, nucleic acidsProteins
ConfigurationLinear/conformational determinantsLinear determinants
Size4-8 residues8-15 residues
NumberLimited, located on the exposed surface of the antigenLimited to those proteins that can be processed and bind to MHC

Types of Epitopes

The antigenic determinants (epitopes) are divided into two categories based on their structures and interaction with the paratope.

  • Linear epitopes
  • Conformational epitopes
Linear and conformational B-cell epitopes. Linear B-cell epitopes (a) are composed of sequential/continuous residues, while conformational B-cell epitopes (b) contain scattered/discontinuous residues along the sequence. (Image source-Ref-1)
PropertiesLinear epitopesConformational epitopes
LocationMost polysaccharides, fibrilar proteins, and single-stranded nucleic acids.Most globular proteins and native nucleic acids
CompositionAdjacent amino acid residues in the covalent sequenceAmino acid residues brought into proximity to one another by folding
Antigen-antibody reactionsDependent on linear structure of 6 amino acidsDependent on the 3-dimensional structure
Availability for antibody interactionBecome available upon denaturation of proteinsUsually associated with native proteins

Epitope Spreading

Epitope spreading or ‘determinant spreading’ denotes ‘development of immune responses to endogenous epitopes secondary to the release of self-antigens during a viral infection or a chronic autoimmune or inflammatory response’. In such conditions, sequestered autoantigens are exposed to autoreactive T cells causing autoimmune disease.

In an animal model study, it was found that animal infected with encephalomyelitis virus shows multiple sclerosis-like disease because self-reactive T cells react with cellular antigens rather than the antigens of the virus.

Mechanism of Epitope spreading

Mechanism of epitope spreading (Image source: Ref-4)

A polypeptide antigen (having multiple epitopes) is processed intracellularly by an antigen-presenting cell and a small peptide fragment is presented to a Th 1 cell. The T cell responds to the peptide by releasing cytokines which stimulates a B cell to produce antibodies specific to the peptide fragment and also express antigen-specific immunoglobulins on the cell surface.

Surface immunoglobulin of B cells subsequently recognize the intact antigen, internalize it, and process it. But, in this case, B cell presents a new peptide epitope via MHC class II to a T cell, thereby initiating the production of different antibodies to a new epitope of the same antigen.

This broadening of the immune response can target epitopes either within the same antigen (intramolecular spreading) or another antigen (intermolecular spreading). Multiple factors are involved in the induction of epitope spreading, such as:

  • enhanced display of previously hidden antigenic determinants under the local inflammatory/cytokine environment
  • Release of self-antigens following tissue damage
  • Role played by B cells as antigen-presenting cells.

Identification of Epitopes

With the availability of newer information about the specific roles played by epitopes and their potential use, research is ongoing to identify epitopes of complex antigens. Epitope identification is a costly and time-consuming process. It requires experimental screening of large arrays of potential epitope candidates.

Epitope identification can provide different benefits such as

  • understanding disease etiology,
  • immune monitoring,
  • developing diagnosis assays,
  • designing epitope-based vaccines

We hope to see breakthrough this is field of research.

References and further readings

  1. Sanchez-Trincado, J. L., Gomez-Perosanz, M., & Reche, P. A. (2017). Fundamentals and Methods for T- and B-Cell Epitope Prediction. Journal of Immunology Research, 2017, 2680160. https://doi.org/10.1155/2017/2680160
  2. Powell, A. M., & Black, M. M. (2001). Epitope spreading: Protection from pathogens, but propagation of autoimmunity? Clinical and Experimental Dermatology, 26(5), 427–433. https://doi.org/10.1046/j.1365-2230.2001.00852.x.
  3. An Introduction to Antibodies: Antigens, Epitopes and Antibodies. (n.d.). Sigma-Aldrich. Retrieved May 31, 2021, from https://www.sigmaaldrich.com/technical-documents/articles/biology/antigens-epitopes-antibodies.html
  4. Epitope spreading. (n.d.). Retrieved June 1, 2021, from https://somepomed.org/articulos/contents/mobipreview.htm?29/48/30471
  5. Cruse, J. M., Lewis, R. E., & Wang, H. (Eds.). (2004). 2—ANTIGENS, IMMUNOGENS, VACCINES, AND IMMUNIZATION. In Immunology Guidebook (pp. 17–45). Academic Press. https://doi.org/10.1016/B978-012198382-6/50026-1
  6. Kuby Immunology, 8th Edition

Acharya Tankeshwar

Hello, thank you for visiting my blog. I am Tankeshwar Acharya. Blogging is my passion. As an asst. professor, I am teaching microbiology and immunology to medical and nursing students at PAHS, Nepal. I have been working as a microbiologist at Patan hospital for more than 10 years.

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